Stomach and intestinal stem cells are located in discrete niches called the isthmus and crypt, respectively. Recent studies have demonstrated a surprisingly conserved role for Wnt signaling in gastrointestinal development. Although intestinal stromal cells secrete Wnt ligands to promote stem cell renewal, the source of stomach Wnt ligands is still unclear. Here, by performing single cell analysis, we identify gastrointestinal stromal cell populations with transcriptome signatures that are conserved between the stomach and intestine. In close proximity to epithelial cells, these perictye-like cells highly express telocyte and pericyte markers as well as Wnt ligands, and they are enriched for Hh signaling. By analyzing mice activated for Hh signaling, we show a conserved mechanism of GLI2 activation of Wnt ligands. Moreover, genetic inhibition of Wnt secretion in perictye-like stromal cells or stromal cells more broadly demonstrates their essential roles in gastrointestinal regeneration and development, respectively, highlighting a redundancy in gastrointestinal stem cell niches.

Graphical Abstract Highlights d Sufu exerts tumor-promoting and -suppressive functions in SHH medulloblastoma d Sufu;Spop double knockout medulloblastoma mouse model unveils GLI2 targetome d ATOH1 and GLI2 cooperate to activate target genes in SHH medulloblastoma SUMMARY SUFU alterations are common in human Sonic Hedgehog (SHH) subgroup medulloblastoma (MB). However, its tumorigenic mechanisms have remained elusive. Here, we report that loss of Sufu alone is unable to induce MB formation in mice, due to insufficient Gli2 activation. Simultaneous loss of Spop, an E3 ubiquitin ligase targeting Gli2, restores robust Gli2 activation and induces rapid MB formation in Sufu knockout background. We also demonstrated a tumor-promoting role of Sufu in Smo-activated MB ($60% of human SHH MB) by maintaining robust Gli activity. Having established Gli2 activation as a key driver of SHH MB, we report a comprehensive analysis of its targetome. Furthermore, we identified Atoh1 as a target and molecular accomplice of Gli2 that activates core SHH MB signature genes in a synergistic manner. Overall, our work establishes the dual role of SUFU in SHH MB and provides mechanistic insights into transcriptional regulation underlying Gli2-mediated SHH MB tumorigenesis. (C) Survival is normal in Sufu KO mice, while Ptch1 KO mice rapidly succumb to MBs. (D) Gene expression profiling by cDNA microarray reveals downregulation of several Gli target genes and moderate expression of some Hh pathway components and MB signature genes in Sufu KO cerebellum at P13, while Ptch1 KO MBs displays upregulation of Hh component genes and full-blown MB signature. See also Figure S1.

Highlights d Sufu and Spop modulate proliferation of gut embryonic progenitors d Mesenchymal Hh signaling plays a permissive role for villus formation d GLI2 directly induces expression of intestinal stromal stem cell niche signals d Mesenchymal reduction of Sufu promotes intestinal tumorigenesis

As a result of an author oversight in the originally published version of this article, the surname of one of the authors, Elly Sau-Wai Ngan, was presented as ''Sau-Wai Ngan'' instead of ''Ngan.'' This error has now been corrected in the article online. The authors regret the error.